Is EXOSC2 p.Arg231Ter (c.691C>T) pathogenic?

EXOSC2 p.Arg231Ter (c.691C>T) is classified Conflicting classifications of pathogenicity in EXOSC2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-02). Ultra-rare (popmax 0.0173%, afr); Associated with retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome.

How common is EXOSC2 p.Arg231Ter (c.691C>T) in the general population?

EXOSC2 p.Arg231Ter (c.691C>T) is ultra-rare (popmax 0.0173%, afr) (gnomAD).

EXOSC2 p.Arg231Ter

Q: What condition is associated with EXOSC2 p.Arg231Ter (c.691C>T)?

EXOSC2 p.Arg231Ter (c.691C>T) is associated with retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome (ClinVar).

c.691C>T · rs149299789 · VCV1496327

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, afr)

Conditions

retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 9
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.97 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4	GERP 2.3, phastCons 1
Overall
CADD	43.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0173% African / African-American · 13/74,982 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00997%

Overall 0.00992% 160/1,613,528 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0173%	5,768
European (non-Finnish)	0.0123%	8,136
Remaining individualsnot grpmax-eligible	0.0032%	31,246

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EXOSC2
Protein: p.Arg231Ter
Coding: c.691C>T
MANE Select: NM_014285
dbSNP: rs149299789
Type: single nucleotide variant
Location: chr9:130703071 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.25 · 8 PDB
Residue 231: an α-helix

Full EXOSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EXOSC2 p.Lys65Asn Uncertain significance ★★ ⚠ same condition
EXOSC2 p.Met5Val Uncertain significance ★★ ⚠ same condition
EXOSC2 p.Tyr206His Uncertain significance ★★ ⚠ same condition
EXOSC2 p.Gly198Asp Likely pathogenic ★ same condition
EXOSC2 p.Trp204Ter Likely pathogenic ★ same condition
EXOSC2 c.673-1G>T Conflicting classifications of pathogenicity ★ same condition
EXOSC2 c.801+1G>A Conflicting classifications of pathogenicity ★ same condition
EXOSC2 p.Arg87Gln Conflicting classifications of pathogenicity ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/exosc2-p-arg231ter (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown